Systemic lupus erythematosus (SLE) is associated with up to a 50-fold increase in the incidence of cardiovascular (CV) events secondary to premature atherosclerosis. Framingham risk factors do not account for this increased propensity and the exact responsible mechanisms remain uncharacterized. We have recently proposed that accelerated CV damage in SLE is due to an imbalance of endothelial cell damage (apoptosis) and repair. We hypothesize that type I interferons (IFNs) play a crucial role in the induction of abnormal vascular repair in SLE and, potentially in the development of vascular damage and premature atherosclerosis in this disease. SPECIFIC AIMS: 1. Characterize the role of type I IFNs on endothelial dysfunction, vascular repair and atherosclerosis development in lupus murine systems. This will be tested by comparing the murine lupus model NZM2328 with the same strain crossed to type I IFNR knock-out (KO) mice (NZM2318/IFNRKO). Endothelium-dependent and independent vascular function and development of arterial inflammatory infiltrates will be evaluated in these mice. Whether administration of recombinant IFN-1 accelerates endothelial dysfunction and promotes atherosclerosis in NZM2328 mice will also be evaluated. 2. Characterize the angiogenenic pathways affected by type I IFNs in murine SLE. The role of type I IFNs on phenotype and function of endothelial progenitor cells (EPCs) will be studied by comparing vasculogenesis in vitro and in vivo on NZM2318 and NZM2318/IFNRKO mice. This will be performed by quantifying EPCs, assessing their capacity to become mature ECs, form and incorporate into vascular structures, and synthesize proangiogenic factors. Microarray analysis will assess the EPC genes affected by type I IFNs in NZM2328 and NZM2318/IFNRKO in specific cellular compartments. Vascular repair molecular pathways that are affected by type I IFNs will be identified. 3. Characterize the role of type I IFNs in endothelial dysfunction and atherosclerosis risk in SLE. The University of Michigan has established a Cardiovascular Lupus Cohort which follows SLE patients prospectively to examine functional, anatomical, cellular and soluble markers of vascular damage and atherosclerotic risk, and the development of CV events. To assess the role of type I IFNs in the development of premature CVD in SLE, the association of type I IFN signatures and IFN-1 expression with endothelial function (FMD/NMD), carotid intimal medial thickness (CIMT), coronary calcification, serum and cellular markers of vascular damage/ repair will be established in this cohort. PUBLIC HEALTH RELEVANCE: The results from this study will characterize mechanisms that promote early cardiovascular disease in patients with lupus and could contribute to the design of therapeutic interventions aimed at decreasing the risk of this potentially fatal complication.